Abstract In this Direct-to-Phase 2 SBIR, Immune-Onc Therapeutics proposes development of IO-202, a safe and active therapy for prolonging the survival of patients with monocytic acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). AML affects 20,000 people in the US each year and has a dismal prognosis, with a 5-year survival rate of approximately 25%. CMML is an established precursor of AML with monocytic differentiation, with approximately 20% of CMML cases progressing to AML. Novel treatments are urgently needed to improve patient outcomes. LILRB4 is an immune-inhibitory receptor whose expression is restricted to normal antigen-presenting cells, where it functions as a negative regulator of immunity; it is upregulated on monocytic subtypes of AML, where it creates an immunosuppressive micro-environment. IO- 202 is an antibody that inhibits LILRB4 signaling; LILRB4 blocking antibodies have resulted in tumor regression, delay in tumor engraftment, and anti-leukemia T-cell activation in preclinical in vivo models of AML, suggesting that IO-202 is a promising therapeutic candidate. The differential in expression levels between normal and AML cells allows us to selectively target the AML cells. We hypothesize that IO-202 will block LILRB4 signaling in leukemic cells in patients with monocytic AML, thereby activating effector T-cells, impeding leukemic engraftment/infiltration and mediating direct leukemic cell killing through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. The aforementioned biological activity is hypothesized to translate into blast count reductions in the bone marrow of patients with AML, leading to complete remissions and prolonged survival. Here, we propose to evaluate the combination therapy of IO-202 with standard cytotoxic chemotherapy, hypomethylating agents and/or targeted therapy in non-clinical AML models (Aim 1). In addition, we aim to characterize the safety, pharmacokinetics and activity of IO-202, an antibody targeting LILRB4, in a first-in-human Phase 1 clinical trial in relapsed/refractory AML and CMML patients. Data from this trial will identify the maximum-tolerated dose (MTD) of IO-202 (Aim 2) and the recommended Phase 2 dose (RP2D) of IO-202 (Aim 3).